Alemtuzumab is a humanized anti-CD52 IgG1 monoclonal antibody that depletes CD52-expressing cells from the circulation. This drug (marketed as Campath, MabCampath or Campath-1H and currently under further development as Lemtrada) is a monoclonal antibody used in the treatment of chronic lymphocytic leukemia (CLL), cutaneous T-cell lymphoma (CTCL) and T-cell lymphoma. It was approved by the US Food and Drug Administration for CLL patients who have been treated with alkylating agents and who have failed fludarabine therapy. Since the approval of the US Food and Drug Administration (FDA) in November 2014, alemtuzumab is approved in over 30 countries for the therapy of relapsing-remitting multiple sclerosis (RRMS). Alemtuzumab demonstrated superiority to subcutaneous (sc) interferon β-1a (IFNβ-1a), an established disease-modifying therapy (DMT) for RRMS. The high efficacy of alemtuzumab, with remarkable effects on clinical and radiological disease outcome parameters is offset by frequent and significant adverse events. Besides infusion-associated reactions (IAR), mild to moderate infections, especially the occurrence of secondary autoimmune disease, has somewhat dampened enthusiasm for alemtuzumab. Approximately 30%-40% of patients develop secondary autoimmune diseases predominantly affecting thyroid, kidney and thrombocytic function.
CD52 is a 21-28 kDa cell surface glycoprotein attached to the cell membrane by a glycosylphosphatidyl-inositol anchor of 12 amino acids. CD52 is one of the most abundant membrane glycoproteins on T and B lymphocytes and is also expressed on natural killer (NK) cells, monocytes, macrophages, dendritic cells, and eosinophilic granulocytes and to a lesser extent on neutrophilic granulocytes. CD52 is not expressed on erythrocytes, platelets, and hematopoietic progenitor cells. The exact function of CD52 is unknown but it is suggested that the molecule may be involved in T lymphocyte co-stimulation, the induction of regulatory T lymphocytes, and T lymphocyte migration and adhesion. Alemtuzumab is an IgG1 kappa with human variable framework and constant regions, and complementarity-determining regions derived from a rat monoclonal antibody. This agent selectively binds to CD52, thereby triggering a host immune response that results in lysis of CD52+ cells. In other words, alemtuzumab induces antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC), and activates pro-apoptotic pathways on CD52-expressing cells. Administration of alemtuzumab causes a profound depletion of T and B lymphocytes, NK cells, dendritic cells, granulocytes, and monocytes by three mechanisms: complement-dependent cytotoxicity (through C1q activation and subsequent generation of the membrane attack complex), antibody-dependent cellular cytotoxicity (after the activation of NK cells and macrophages through their IgG fragment C receptor), and induction of apoptosis. Depletion of peripheral lymphocytes occurs within 1h after alemtuzumab administration. Lymphocyte depletion from secondary lymphoid tissues occurs over 3-5 days. Alemtuzumab administration significantly depletes peripheral monocytes and NK cells.
Fig 1. Mechanism of Action of Alemtuzumab
Table 1. Clinical Projects of Alemtuzumab*
NCT ID | Status | Conditions | Lead Sponsor | Update Time |
NCT03302754 | Recruiting | Allogeneic Hematopoietic Cell Transplantation | Children's Hospital Medical Center, Cincinnati | October 5, 2017 |
NCT03135249 | Recruiting | Multiple Sclerosis (MS) | University of Texas Southwestern Medical Center | May 1, 2017 |
NCT03193086 | Recruiting | Multiple Sclerosis | Glostrup University Hospital, Copenhagen | June 20, 2017 |
NCT03477500 | Recruiting | Multiple Sclerosis | Haukeland University Hospital | March 26, 2018 |
NCT03784898 | Recruiting | Multiple Sclerosis | Genzyme, a Sanofi Company | December 24, 2018 |
NCT00858117 | Active, not recruiting | Leukemia | Northwestern University | March 9, 2009 |
NCT02689453 | Recruiting | T-Cell Lymphoma Relapsed, Adult T-Cell Leukemia (ATL), Peripheral T-Cell Lymphoma (PTCL), Cutaneous T Cell Lymphoma (CTCL), T-Cell Prolymphocytic Leukemia | National Cancer Institute (NCI) | February 24, 2016 |
NCT02419378 | Recruiting | Multiple Sclerosis, Relapsing-Remitting | University Hospital Muenster | April 17, 2015 |
NCT03774914 | Recruiting | Multiple Sclerosis | Genzyme, a Sanofi Company | December 13, 2018 |
NCT03368664 | Recruiting | Multiple Sclerosis | Genzyme, a Sanofi Company | December 11, 2017 |
NCT02385110 | Recruiting | Leukemia | M.D. Anderson Cancer Center | March 11, 2015 |
NCT03806387 | Recruiting | Multiple Sclerosis | University of Aarhus | January 16, 2019 |
NCT00069238 | Active, not recruiting | Lymphoma, T-Cell; Lymphoma, Extranodal NK-T-Cell | National Cancer Institute (NCI) | September 18, 2003 |
NCT02583594 | Active, not recruiting | Progressive Multiple Sclerosis | Genzyme, a Sanofi Company | October 22, 2015 |
NCT00345345 | Active, not recruiting | T-LGL Lymphoproliferative Disorders | National Heart, Lung, and Blood Institute (NHLBI) | June 28, 2006 |
NCT02472054 | Recruiting | Hemophagocytic Lymphohistiocytosis (HLH) | Assistance Publique - Hôpitaux de Paris | June 15, 2015 |
NCT01465334 | Active, not recruiting | CLL, SLL | Dana-Farber Cancer Institute | November 4, 2011 |
NCT01361711 | Active, not recruiting | Stage I Chronic Lymphocytic Leukemia, Stage II Chronic Lymphocytic Leukemia, Stage III Chronic Lymphocytic Leukemia, Stage IV Chronic Lymphocytic Leukemia | Northwestern University | May 27, 2011 |
NCT00195624 | Active, not recruiting | Severe Aplastic Anemia, Refractory; Severe Aplastic Anemia, Relapse | National Heart, Lung, and Blood Institute (NHLBI) | September 19, 2005 |
NCT01030900 | Active, not recruiting | Hodgkin Lymphoma, Diffuse Large B-Cell Lymphoma | National Cancer Institute (NCI) | December 14, 2009 |
NCT02255656 | Active, not recruiting | Relapsing Remitting Multiple Sclerosis | Genzyme, a Sanofi Company | October 2, 2014 |
NCT00040846 | Active, not recruiting | Leukemia | Fred Hutchinson Cancer Research Center | January 27, 2003 |
NCT03647722 | Recruiting | Multiple Sclerosis | University of Southern California | August 27, 2018 |
NCT02623946 | Active, not recruiting | Multiple Sclerosis | Clinique Neuro-Outaouais | December 8, 2015 |
NCT00553098 | Active, not recruiting | Immunodeficiency Syndrome, Non-Cancer Diagnosis | Fred Hutchinson Cancer Research Center | November 5, 2007 |
NCT01120028 | Active, not recruiting | Kidney Transplantation | University of Oxford | May 10, 2010 |
NCT03591380 | Recruiting | Kidney Transplantation | University of Wisconsin, Madison | July 19, 2018 |
NCT03250169 | Recruiting | Multiple Sclerosis | Queen Mary University of London | August 15, 2017 |
NCT03587272 | Recruiting | Sickle Cell Disease | Allistair Abraham, MD | July 16, 2018 |
NCT01729494 | Active, not recruiting | Renal Transplantation | University of Cincinnati | November 20, 2012 |
NCT03910452 | Not yet recruiting | Chronic Granulomatous Disease | National Institute of Allergy and Infectious Diseases (NIAID) | April 10, 2019 |
NCT00408447 | Recruiting | Sickle Cell Disease, Beta Thalassemia | Columbia University | December 7, 2006 |
NCT01659606 | Recruiting | Dyskeratosis Congenita, Hoyeraal Hreidarsson Syndrome, Revesz Syndrome, Aplastic Anemia | Boston Children’s Hospital | August 8, 2012 |
NCT03421756 | Recruiting | Sickle Cell Disease | Kathleen Dorritie | February 5, 2018 |
NCT03214354 | Recruiting | Sickle Cell Disease, Stem Cell Transplant Complications, Red Blood Cell Disorder, Pure Red Cell Aplasia | University of Calgary | July 11, 2017 |
NCT00920972 | Recruiting | Metabolic Disorders, Hematologic, Immune, or Bone Marrow Disorders, Hemoglobinopathies, Non-malignant Disorders | Washington University School of Medicine | June 16, 2009 |
NCT00565773 | Active, not recruiting | Organ Transplantation | Emory University | November 30, 2007 |
NCT00619528 | Active, not recruiting | Immunosuppression, Kidney Transplantation, Graft Rejection | Northwestern University | February 21, 2008 |
NCT01877837 | Active, not recruiting | Sickle Cell Disease | Hackensack Meridian Health | June 14, 2013 |
NCT01897688 | Active, not recruiting | Type 1 Diabetes, Severe Hypoglycemic Unawareness | Northwestern University | July 12, 2013 |
NCT02626715 | Recruiting | Acute Myeloid Leukemia (AML), Myelodysplastic Syndrome (MDS), Hematopoietic Stem Cell Transplant (HSCT) | Randy Windreich | December 10, 2015 |
NCT01821781 | Recruiting | Immune Deficiency Disorders, Severe Combined Immunodeficiency, Chronic Granulomatous Disease, X-linked Agammaglobulinemia, Wiskott-Aldrich Syndrome, Hyper-IgM, DiGeorge Syndrome, Chediak-Higashi Syndrome, Common Variable Immune Deficiency, Immune Dysregulatory Disorders, Hemophagocytic Lymphohistiocytosis, IPEX, Autoimmune Lymphoproliferative Syndrome, X-linked Lymphoproliferative Syndrome | Washington University School of Medicine | April 1, 2013 |
NCT00426517 | Recruiting | Inherited Immune Deficiencies | National Institute of Allergy and Infectious Diseases (NIAID) | January 24, 2007 |
NCT03504241 | Recruiting | Kidney Transplantation, Renal Transplantation, Renal Transplant Recipient | National Institute of Allergy and Infectious Diseases (NIAID) | April 20, 2018 |
NCT01050855 | Recruiting | Non-Malignant Diseases, Immunodeficiencies, Hemoglobinopathies | Children's Hospital of Philadelphia | January 18, 2010 |
NCT01935128 | Active, not recruiting | Renal Transplant | University of Toledo Health Science Campus | September 4, 2013 |
NCT02867800 | Recruiting | Sickle Cell Disease, Graft Versus Host Disease | Monica Bhatia | August 16, 2016 |
NCT02435901 | Active, not recruiting | Sickle Cell Disease, Beta Thalassemia-Major | Northwell Health | May 6, 2015 |
NCT02678143 | Recruiting | Sickle Cell Disease | Washington University School of Medicine | February 9, 2016 |
NCT00061568 | Recruiting | Congenital Hemolytic Anemia, Sickle Cell Disease | National Heart, Lung, and Blood Institute (NHLBI) | May 29, 2003 |
NCT00368355 | Recruiting | Acute Lymphoblastic Leukemia, Non Hodgkins Lymphoma, Myelodysplastic Syndrome, Acute Myeloid Leukemia, Chronic Myelogenous Leukemia, Hemophagocytic Lymphohistiocytosis (HLH), Familial Hemophagocytic Lymphohistiocytosis (FLH), Viral-associated Hemophagocytic Syndrome (VAHS), X-linked Lymphoproliferative Disease (XLP) | Baylor College of Medicine | August 24, 2006 |
NCT01962415 | Recruiting | Primary Immunodeficiency (PID), Congenital Bone Marrow Failure Syndromes, Inherited Metabolic Disorders (IMD), Hereditary Anemias, Inflammatory Conditions | Paul Szabolcs | October 14, 2013 |
NCT02105766 | Recruiting | Sickle Cell Disease, Thalassemia, Stem Cell Transplantation, Graft vs Host Disease | National Heart, Lung, and Blood Institute (NHLBI) | April 7, 2014 |
NCT03821610 | Recruiting | Acute Lymphoblastic Leukemia | University of Birmingham | January 30, 2019 |
NCT00977691 | Active, not recruiting | Sickle Cell Anemia | National Heart, Lung, and Blood Institute (NHLBI) | September 16, 2009 |
NCT02038478 | Recruiting | Sickle Cell Disease and Thalassemia | University of Texas Southwestern Medical Center | January 16, 2014 |
NCT03535298 | Recruiting | Multiple Sclerosis, Relapsing-Remitting | The Cleveland Clinic | May 24, 2018 |
NCT03182426 | Recruiting | Diabetes Mellitus, Type 1 | University of Alberta | June 9, 2017 |
NCT03194321 | Recruiting | End Stage Renal Disease | Cedars-Sinai Medical Center | June 21, 2017 |
NCT02497404 | Recruiting | Leukemia, Erythroblastic, Acute, Myelodysplastic Syndromes | Weill Medical College of Cornell University | July 14, 2015 |
NCT00566696 | Active, not recruiting | Leukemia, Acute Lymphocytic (ALL); Leukemia, Myeloid, Acute(AML); Leukemia, Myeloid, Chronic(CML); Juvenile Myelomonocytic Leukemia (JMML); Hemoglobinuria, Paroxysmal Nocturnal (PNH); Hodgkin Lymphoma; Lymphoma, Non-Hodgkin (NHL); Myelodysplastic Syndrome (MDS) | St. Jude Children's Research Hospital | December 3, 2007 |
NCT01625351 | Active, not recruiting | Ewing Sarcoma, Gastrointestinal Tumor, Germ Cell Tumor, Hepatic Tumor, Lymphoma, Wilms Tumor, Rhabdoid Tumor, Clear Cell Carcinoma, Renal Cell Carcinoma, Melanoma, Neuroblastoma, Rhabdomyosarcoma, Non-rhabdomyosarcoma | St. Jude Children's Research Hospital | June 21, 2012 |
NCT02059239 | Recruiting | Hodgkin's Lymphoma, Non-Hodgkin's Lymphoma | Weill Medical College of Cornell University | February 11, 2014 |
NCT02061800 | Recruiting | Chronic Myeloid Leukemia (CML), Acute Myelogenous Leukemia (AML), Myelodysplastic Syndrome (MDS), Juvenile Myelomonocytic Leukemia (JMML), Acute Lymphoblastic Leukemia (ALL), Lymphoma (Hodgkin's and Non-Hodgkin's) | Diane George, MD | February 13, 2014 |
NCT01256398 | Active, not recruiting | Acute Lymphoblastic Leukemia, Adult B Acute Lymphoblastic Leukemia With t (9;22) (q34.1; q11.2); BCR-ABL1, Untreated Adult Acute Lymphoblastic Leukemia | National Cancer Institute (NCI) | December 8, 2010 |
NCT00176852 | Active, not recruiting | Sickle Cell Disease, Thalassemia, Severe Congenital Neutropenia, Diamond-Blackfan Anemia, Shwachman-Diamond Syndrome | Masonic Cancer Center, University of Minnesota | September 15, 2005 |
NCT02162420 | Recruiting | Dyskeratosis Congenita, Aplastic Anemia | Masonic Cancer Center, University of Minnesota | June 12, 2014 |
NCT01652092 | Recruiting | SCID, Omenn's Syndrome, Reticular Dysgenesis, Wiskott-Aldrich Syndrome, Bare Lymphocyte Syndrome, Common Variable Immunodeficiency, Chronic Granulomatous Disease, CD40 Ligand Deficiency, Hyper IgM Syndrome, X-linked Lymphoproliferative Disease, Hemophagocytic Lymphohistiocytosis, Griscelli Syndrome, Chediak-Higashi Syndrome, Langerhan's Cell Histiocytosis | Masonic Cancer Center, University of Minnesota | July 27, 2012 |
NCT03630211 | Recruiting | Systemic Sclerosis, Diffuse Sclerosis Systemic, Interstitial Lung Disease, Pulmonary Hypertension | Paul Szabolcs | August 14, 2018 |
NCT01909245 | Recruiting | Type 1 Diabetes Mellitus | City of Hope Medical Center | July 26, 2013 |
NCT03500731 | Recruiting | Idiopathic Pulmonary Fibrosis, Emphysema or COPD | Paul Szabolcs | April 17, 2018 |
NCT03444064 | Recruiting | Diabetes, Diabetes Mellitus, Type 1 | University of Alberta | February 23, 2018 |
NCT03653338 | Recruiting | Sickle Cell Anemia, Beta-thalassemia Major, Diamond-blackfan Anemia | Beth Carella, DO | August 31, 2018 |
NCT00924170 | Active, not recruiting | Adult T-Cell Leukemia (ATL) | National Cancer Institute (NCI) | June 18, 2009 |
NCT03128996 | Recruiting | Severe Sickle Cell Disease, Bone Marrow Failure Syndromes, Metabolic Disorders, Immunologic Disorders, Hemoglobinopathies, Non-malignant Disorders | Washington University School of Medicine | April 26, 2017 |
NCT03784547 | Not yet recruiting | Multiple Sclerosis | Hospital Italiano de Buenos Aires | December 24, 2018 |
NCT01240525 | Active, not recruiting | Graft Versus Host Disease, Leukemia, Lymphoma, Myeloma, Myelodysplastic Syndrome | University College, London | November 15, 2010 |
NCT01247701 | Active, not recruiting | Myeloid Hematological Malignancies | Baylor College of Medicine | November 24, 2010 |
NCT01013441 | Active, not recruiting | Chronic Lymphocytic Leukemia | University of Pennsylvania | November 13, 2009 |
NCT00692939 | Recruiting | Crohn's Disease | Paul Szabolcs | June 6, 2008 |
NCT01966367 | Recruiting | Bone Marrow Failure Syndrome, Severe Aplastic Anemia, Severe Congenital Neutropenia, Amegakaryocytic Thrombocytopenia, Diamond-Blackfan Anemia, Schwachman Diamond Syndrome, Primary Immunodeficiency Syndromes, Acquired Immunodeficiency Syndromes, Histiocytic Syndrome, Familial Hemophagocytic Lymphocytosis, Lymphohistiocytosis, Macrophage Activation Syndrome, Langerhans Cell Histiocytosis (LCH), Hemoglobinopathies, Sickle Cell Disease, Sickle Cell-beta-thalassemia | Diane George, MD | October 21, 2013 |
NCT01889381 | Recruiting | Facial Injuries, Traumatic Wounds and Injuries, Craniofacial Injuries, Craniofacial Defects | Johns Hopkins University | June 28, 2013 |
NCT01862965 | Active, not recruiting | Chronic Graft-versus-host Disease | Universitätsklinikum Hamburg-Eppendorf | May 27, 2013 |
NCT02179359 | Recruiting | Sickle Cell Disease, Transfusion Dependent Alpha- or Beta-, Thalassemia, Diamond Blackfan Anemia, Paroxysmal Nocturnal Hemoglobinuria, Glanzmann Thrombasthenia, Severe Congenital Neutropenia, Shwachman-Diamond Syndrome, Non-Malignant Hematologic Disorders | Masonic Cancer Center, University of Minnesota | July 1, 2014 |
NCT02629120 | Recruiting | X-Linked Chronic Granulomatious Disease | National Institute of Allergy and Infectious Diseases (NIAID) | December 14, 2015 |
NCT03500328 | Recruiting | Multiple Sclerosis, Relapsing-Remitting | Johns Hopkins University | April 17, 2018 |
NCT01459107 | Recruiting | Amputation, Traumatic, Wounds and Injuries, Hand Injuries | Johns Hopkins University | October 25, 2011 |
NCT01949129 | Recruiting | Acute Lymphoblastic Leukaemia | St. Anna Kinderkrebsforschung | September 24, 2013 |
NCT03077542 | Enrolling by invitation | Sickle Cell Disease | National Heart, Lung, and Blood Institute (NHLBI) | March 13, 2017 |
NCT03193866 | Recruiting | Relapsing-remitting Multiple Sclerosis | Karolinska Institutet | June 21, 2017 |
NCT00889798 | Active, not recruiting | Non-Hodgkin's Lymphoma (NHL), Chronic Lymphocytic Leukemia (CLL), Multiple Myeloma (MM) | iOMEDICO AG | April 29, 2009 |
NCT02171104 | Recruiting | Metabolic Disorders | Masonic Cancer Center, University of Minnesota | June 23, 2014 |
NCT03444805 | Not yet recruiting | Autoimmune Diseases | European Group for Blood and Marrow Transplantation | February 23, 2018 |
NCT03836690 | Not yet recruiting | Lymphoma, Leukemia, Myeloma, Myelodysplastic Syndromes Severe Aplastic Anemia, Primary Immune Deficiency, Graft Vs Host Disease | University College, London | February 11, 2019 |
Table 2. Approved Drugs of Alemtuzumab**
INN (trade name) | Therapeutic area | Dose | Strength | Route | Company | Marketing start | Market |
Compath | B-cell chronic lymphocytic leukemia | VIAL | 10MG/ML | Intravenous | Genzyme | June 23, 2000 |
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Lemtrada | Relapsing forms of multiple sclerosis (MS) | Injection | 12MG/1.2ML | Intravenous infusion | Genzyme | September 17, 2017 |
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Reference
*The table was excerpted from the following website
https://clinicaltrials.gov/ct2/results?term=Alemtuzumab
**Information presented in the table were collected from the following website:
https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=103948
For research use only. Not intended for any clinical use.